Project Summary Polycystic ovary syndrome (PCOS) is the most highly prevalent endocrine disorder affecting women. It is defined by the presence of hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovarian morphology. Importantly, PCOS is the most common cause of anovulatory infertility. Despite extensive study, the pathophysiology underlying PCOS remains incompletely understood. A hallmark of PCOS is neuroendocrine dysfunction: women with PCOS demonstrate consistently increased gonadotropin-releasing hormone (GnRH) pulse frequency, which promotes luteinizing hormone (LH) excess and relative follicle-stimulating hormone (FSH) deficiency?both of which contribute to HA and ovulatory dysfunction. Rapid GnRH frequency is in part related to relative resistance to progesterone (P4) negative feedback. Our prior research demonstrated that such resistance to P4 negative feedback can be reversed with androgen-receptor blockade. Ovulation relies upon the midcycle gonadotropin surge, which occurs in response to positive feedback from high estradiol (E2) levels and a preovulatory increase in P4 levels. To date, little is known regarding the potential existence of HA- mediated defects in sex steroid positive feedback and gonadotropin surge generation in women with PCOS. However, our preliminary data in 8 women with PCOS and 11 normally-cycling women indicate that sex steroid positive feedback may be dysfunctional in PCOS. These data demonstrate a significant deficit in gonadotropin response to administration of P4 in E2-pretreated women with PCOS as compared to E2-pretreated control women. The research proposed herein will address the hypotheses that (a) HA antagonizes the positive feedback actions of P4 on gonadotropin secretion and (b) PCOS is associated with defects in E2 positive feedback actions on gonadotropin secretion. In the proposed studies, we will (1) examine P4 positive feedback on gonadotropin secretion in PCOS, both at baseline and after 4 weeks of androgen-receptor blockade with flutamide; (2) assess how excess adiposity influences P4 positive feedback by comparing P4 positive feedback among overweight/obese women with PCOS, overweight/obese controls, and lean controls; and (3) evaluate potential defects in E2 positive feedback in PCOS by comparing E2-induced gonadotropin surge generation in PCOS vs. BMI-matched controls. By identifying novel pathways through which PCOS ovulatory dysfunction occurs, the results of this work may establish new approaches for enhancing ovulation induction rates, thereby improving the success of fertility treatments in PCOS.